Almost everything we know about the world is relayed to layer 4 of our neocortex by the thalamus, via the thalamocortical synapse. The neocortex is responsible for transforming these sensory inputs into the conscious experience we call perception; understanding these transformations is therefore essential for understanding both normal and pathological states of consciousness. GABA-releasing inhibitory interneurons are vital participants in these transformations. In primary sensory cortical areas, thalamocortical inputs strongly activate inhibitory interneurons, which in turn provide disynaptic inhibition to neighboring excitatory neurons. This "feedforward" inhibition holds the cortical response under a powerful but dynamically modulated control, and transforms sensory inputs into spatiotemporal activity patterns. The two largest and best studied GABAergic subtypes are parvalbumin-expressing (PV+), which are "fast spiking" (FS) interneurons, and somatostatin-expressing (SOM+) interneurons. Currently, feedforward thalamocortical inhibition is thought to be mediated solely by PV+, FS interneurons; however, this "one interneuron fits all" model is difficult to reconcile with the need to adjust cortical responses to different behavioral states. Indeed, our preliminary results indicate that, contrary to previous reports, both PV+ and SOM+ interneurons receive direct thalamocortical excitation, albeit with very different temporal dynamics. Our central hypothesis is therefore that both PV+ and SOM+ interneurons mediate feedforward thalamocortical inhibition, but with markedly different spatial and temporal properties, and are therefore likely to contribute differentially to thalamocortical transformations, possibly participating in different behavioral states. To test this hypothesis, we will use novel transgenic mice which we have generated, and in which layer 4 SOM+ interneurons express Green Fluorescent Protein. The hypothesis will be tested by recording electrophysiologically synaptic responses corresponding to the three legs of the thalamocortical "triad" - thalamocortical inputs onto inhibitory interneurons, inhibitory inputs onto layer 4 excitatory neurons, and thalamocortical inputs onto layer 4 excitatory neurons. The results of the proposed study will advance our understanding of the neuronal elements and synaptic circuits that mediate sensory perception, and how they operate during normal and abnormal behavioral states. [unreadable] [unreadable] [unreadable]